TRIAZOLE SUBSTITUTED QUINOLINE DERIVATIVES

Abstract: The invention relates to pharmaceutical compositions for the treatment or prevention of lesions of gastrointestinal mucous membranes and having secretion inhibiting, cytoprotective activities. The compositions contain in a biologically effective quantity a triazole-group-substituted quinoline derivative of general formula (I), R<1> stands for a 1-triazolyl-group in position 2 or 4 or a 3-triazolyl-thio or a 5-/C1-4-alkyl/-3-triazolyl-thio-group, R<2> stands for a hydrogen atom in position 3 or optionally in position 2, or for a C1-4-alkyl-group, R<3> stands for a hydrogen atom or for a C1-4-alkyl-group, X stands for a hydrogen or halogen-atom or for a C1-4-alkyl-group or its salts. The invention includes processes for the preparation of the above compositions, and methods for treatment of patients in need of such treatment by administering the substance or the composition. The preferred substance of formula (IV) is also subject of the invention.

Description: Triazole Substituted Quinoline Derivatives. The invention is related to pharmaceutical compositions for protection and treatment of lesions of gastrointestinal mu¬ cous membrans and having secretion inhibiting and cytopro¬ tective activity- More particularly the invention is related to pharmaceutical compositions containing as active ingre¬ dient certain quinoline derivatives and their salts in a biologically effective quantity optionally together with other active pharmaceutical ingredients, processes for their preparation and methods of treatment to use them alone or in combination with other pharmaceutically active ingre¬ dients. In this specification the substituents of varying interpre¬ tation stand always for the following: -R 1 stands for a 1-triazolyl-group in position 2 or 4, or a 3-triazolyl-thio-group or a 5-/Cι- 4 -alkyl/-3-triazolyl-thio-group, -R 2 stands for a hydrogen atom in position 3 or optionally in position 2 or for a Cι-4-alkyl-group, -R 3 stands for a hydrogen atom or a Cι-4-alkyl-group, -X stands for a hydrogen or halogen-atom or for a C1- 4 - alkyl group- It is accepted knowledge that peptic ulcer of the upper di¬ gestive tract is caused as a result of a disequilibrium between the defensive factors (force of mucosal resistance) and agressive factors (gastric acid and pepsin secretion) /e.g. Nature 236, 358,1972/. Pharmaceuticals inhibiting secretion are well known. Part of them are anticholinergs and histamine H2~receptor antagonists such as e.g. cimeti- din, ranitidine, famotidin, others are potassium ATP-ase in¬ hibitors such as omeprasole. These drugs are effective against gastric and intestinal ulcer however on terminating their administration the ulcers reappear in a high ratio of patients especially in cases where the patients do not re¬ ceive antiacidic drugs (Med.Res.Rev.10. , 1, 1990). Another possibility to fight against ulcer resides in the intensification of the protective factors. Protective mecha¬ nism is accomplished through the mucosal barrier which pro- tects the gastric mucous membran from the noxious ef¬ fects of the luminal pepsin and hydrogen ions. The protecti¬ on stands under a multifactoral control: a mucous protective layer covering the gastric mu¬ cous membran which ensures a non-mixing layer on the surface, - bicarbonate secretion, causing a pH-change between the lumen of the stomach (pH=2,0) and the center of the mucous membran cells (pH=7), regeneration of the mucous membran and blood supply from the submucosa. All four of the above are influenced by the synthesis of the so called cytoprotective prostaglandins. (Contemporary is¬ sues in Gastroenterology Vol 3, Chapters 5 to 8, New York, 1985, Ed: Cohen and Saloway). The non-steroidal antiinflammatory drugs (NSAID) like aspi¬ rin, indomethacin, naproxen, piroxicam etc. act by inhibiting the activity of the cyclooxygenase enzyme controlling the synthesis of prostaglandins to a different extent. However it has been shown that as a consequence of inhibiting acti¬ vity of the cyclooxygenase during treatment with NSAIDs, the local prostaglandin E2 concentration of the gastric mu¬ cous membran is decreased resulting in erosions and ulcers (e.g. Lancet,!, 1253 - 54, 1978). There are but some prostaglandin derivatives known (e.g. mi- soprostol) which were able to stop the damage of the gast¬ ric mucous membran when administered after NSAID treatment (Scand. J. Gastroenterol. 9_.page 751, 1974; 94. / page 1973, 1988). Most of the known gastroprotectives however have to be administered before NSAID treatment. Thus there is a need for an effective biological agent which is able on the one side to decrease gastric acidity and on the other hand to intensify the protective factors of the mucosa. This might result in a drug which might be admini¬ stered together or after NSAID treatment for effective pre¬ vention or therapy of gastroenteropathy induced by NSAIDs. One object of the present invention are pharmaceutical com¬ positions for the treatment or prevention of lesions of ga- strointestinal mucous membrans having secretion inhibiting and cytoprotective activities containing in a biologically effective quantity a triazole-group-substituted quinoline derivative of general formula (I) or its salts. According to a previous patented invention a greater group of certain quinoline-deriva ives containing a triazole groups was disclosed including also those of general formula (I) . Their use as analgesics and antiphlogistics was shown on various pharmacological tests along with their fungista- tic activity against phytopathogenic fungal pests (EP 0221947 or corresponding USP 5,104,884). When further investigating said agents we have found that some of the substances, namely the compounds of general for¬ mula (I) are exhibiting a considerable gastroprotective ac¬ tivity. It was highly unexpected to find a smaller group of substances showing gastroprotective activity in a group of antiinflammatories acting supposedly on cyclooxygenase in¬ hibiting basis (the NSAIDs known hitherto were all consi¬ dered cyclooxygenase inhibitors). This is suggesting that the gastroprotecting activity found has a different mecha¬ nism of activity as compared with those known to date. We have investigated the substances against several types of experimental ulcers showing different pathomechanisms. The details of the investigations and results are shown in Bio¬ logical Examples 1.1. to 1.8. The results can be summarized as follows: 1. The compounds inhibit to a high degree, significantly, in a dose-dependent manner the injuries of the mucose caused by NSAIDs such as indomethacin, naproxen, piroxicam (Tables I and II) 2. The substances reduce secretion of the gastric acid as shown on Shay rats both on basic gastric acid secretion and on secretion stimulated with histamine (Tables III and IV). Both quantity of the gastric acid and acidity are decreased as a consequence of treatment. 3. The substances have cytoprotective activity. When severe necrosis, deep ulcer was caused on glandular parts of the gastric region by treatment with hydrochloric acid in etha- nol these were brought into equilibrium by the substances according to the invention as shown in Table V in comparison with cimetidin. The latter was used in standard doses of 100 g/kg and found practically ineffective in this test. The substances inhibit increase of permeability of the inju¬ red blood-vessels in a significant manner when administered in 10 and 20 mg/kg doses as shown on substance 1 in Table VI. This mechanism may play an important role in the anti- ulcer activity of our substances. 4. Significant inhibition of gastric mucous membran lesions caused by stress situations was found in 10 - 25 - 50 mg/kg oral doses as shown in Table VII. 5. It was found further that some of the substances cause a significant increase of the gastric blood supply in the re¬ gion of the corpus and the atrum. This could be shown using the method of Sapistain with Rb*-* 6 isotope investigations as stated in Table VIII. Summarizing the above it is clear that the substances acco¬ rding to the invention show strong and lasting activity on ulcer models having different activity mechanisms. Their spectrum of activity is broad. They develop their protective activity both in a profilactic manner and when given after certain inductive agents and they promote natural healing of ulcers and erosions. On the basis of the above finding we suppose that our sub¬ stances show a unique mechanism of activity and that the substances do not fit easily into any known group of ulcer- inhibiting drugs. Eg: Their inhibiting activity on hyperaci¬ dity is independent from the blocade of the cholinerg and the H2- receptors. Their activity against ethanol + hydro¬ chloric acid gives led to our supposition that cytoprotecti¬ ve activity has to be present. The increased mucosal blood microcirculation has to be one of the factors resulting in this cytoprotective activity along with other unknown furt¬ her correlations etc. The products according to the invention thus might be used in prevention and treatment of lesions of the gastrointest¬ inal mucous me brans, ulcers, erosios based on different pa- thomechanisms. They act favourably on both active and defen¬ sive ulcer-influencing factors. They are a possibility of a new way in ulcer therapy. Preferred pharmaceutical compositions according to the in¬ vention are those containing a quinoline derivative of gene¬ ral formula (II) or its salts in a biologically effective quantity. Another advantageous group of the above compositions acco¬ rding to the invention are compositions containing a quino¬ line derivative of general formula (III) or its salts in a biologically effective quantity. Some of the substances which can be used as such or as salts in a biologically effective quantity in compositions accor¬ ding to the invention are the following: 4- 1H-1,2,4-triazole-l-yl)-quinoline, 4- 1H-1,2,4-triazole-l-yl)-7-halogen-quinolines, 4- 1H-1,2,4-triazole-l-yl)-7-chloro-quinoline, 4- 1H-1,2,4-triazole-l-yl)-7-(Cι- 4 alkyl)-quinolines, 2-methyl-4-(1H-1,2,4-triazole-l-yl)-quinoline, 2-(1H-1,2,4-triazole-l-yl)-quinoline, 2-(1H-1,2,4-triazole-l-yl)-3-(Cι-4alkyl)-quinolines, 2-(1H-1,2,4-triazole-l-yl)-3-methyl-quinoline, 2-(lH-l,2,4-triazole-l-yl)-3-(Cι-4alkyl)-7-halogen- quinolines, 2-(1H-1,2,4-triazole-l-yl)-3-methyl-7-bromo-quinoline, 2-(1H-1,2,4-triazole-l-yl)-3-methyl-7-chloro-quinoline, 2-(lH-l,2,4-triazole-l-yl)-3-(Cι- 4 alkyl)-7-(Cι-4alkyl)- quinoline, 2-(1H-1,2,4-triazole-l-yl)-3-methyl-7-ethyl-quinoline, 2-(Cι_ 4 alkyl)-4-(1H-1,2,4-triazole-l-yl-thio)- quinoline, 2,5,7-trimethyl-4-(5-ethyl-lH-l,2,4-triazole-3-yl-thio)-quinoli 2-(lH-l,2,4-triazole-3-yl-thio)-3-(Cι-4alkyl)-quinolines, 2-(5-ethyl-lH-l,2,4-triazole-3-yl-thio)-3-methyl-quinoline, 2-(1H-1,2,4-triazole-3-yl-thio)-3-methyl-quinoline. One or more substances of Formula (I) can be incorporated into the compositions. The salts may be formed with any pharmaceutically acceptable acid. Acids of preference are e.g. hydrochloric acid, sulfuric acid, ortho-phosphoric acid, oxalic acid, citric acid, maleic acid, tartaric acid and the like. A further embodyment of the present invention are pharmaceu¬ tical compositions for the treatment or prevention of lesi¬ ons of gastric mucous membrans and having secretion inhibi¬ ting, cytoprotective activities containing a quinoline deri¬ vative of general formula (I) or its salts in a biologicaly effective quantity together with inert, pharmaceutically acceptable accompanying products or in admixture with the same. Another further feature of the invention are processes for the preparation of the above pharmaceutical compositions of secretion inhibiting, cytoprotective activity, especially for the treatment or prevention of ulcer by way of formula¬ ting the active ingredient of general formula (I) by admix¬ ture with accompanying and/or additive products usually used in pharmaceutical production. The compositions may appear in any known pharmaceutically acceptable form for direct administration perorally, rec- tally, or by injections or other ways. A further embodyment of the present invention is a method for treatment or prevention of lesions of the gastrointest¬ inal mucous membrans with inhibition of secretion and with cytoprotection by administering to the patient in need of such treatment a quinoline derivative of general formula (I) or its salts preferably orally or rectally in a daily dose of 5 to 30 mg active ingredient per kg body weight. The composition according to the invention may contain at least one of the compounds of general formula (I) or its salts with no further biologically active ingredient. Howe¬ ver according to a further embodyment of the present inven¬ tion compositions are provided containing further biologi¬ cally active ingredients preferably active ingredients ha¬ ving antiinflammatory activity. The substances according to the invention may be administered before or after or paral¬ lel with administration of the antiinflammatory agent. The compounds according to our invention can be prepared ac¬ cording to known methods /EP 0221947 or USP 5,104,884/. However in the following chemical examples are given for the preparation of the most important substances. The compound of formula (IV) is one preferred substance which can be used according to the present invention. Since this compound was not disclosed in the above patent specifications preparati¬ on and characteristics of this chemical substance are given in detail and protection of this substance and its salts is one further aspect of the present invention. The compositions according to the invention can be used orally, parenterally in intramuscular or intravenous inje- ctables or rectally. A transdermal application is also pos¬ sible using known transdermal means, compositions and/or ad¬ ditives. The dose of administration highly depends from the patient, severity of the case and the mode of administration. For oral treatment daily doses starting from 1,0 mg/kg body weight to 200 mg/kg body weight can be used. It is prefera¬ ble to use a daily dose of 5 to 30 mg active ingredient per kg body weight. One dosage unit may contain 10-250 mg preferably 30 to 150 mg of the active ingredient/s/ for oral use. For parenteral use one dose unit contains 1 to 75 mg of the active ingre¬ dient, preferably 5-30 mg per unit. The content of the active ingredient in the compositions ac¬ cording to the invention may vary from about 0,01 to about 99,99 % and accordingly the auxiliary products in the compo¬ sitions may amount to about 99,99 to 0,01 %. In order to prepare the compositions according to the inven¬ tion liquid or solid additive material can be used. The pro¬ ducts may be in form of tablets, dragees, pills, capsules, powders, solutions, suspensions, elixirs. They may be formu¬ lated as controlled release tablets. Carriers used in the compositions according to the inventi¬ on may be different oils, preferably of animal or plant ori¬ gin or synthetic oils. Preferred are hazel-nut oil, soy oil, sesame oil etc. Further liquid carriers especially for in- jectables are water, a physiological salt solution, an aqueous dextrose solution, glycole etc. Further pharmaceutically acceptable carriers and auxiliary products are starch, cellulose, talc, glucose, lactose, saccharose, gelatin, malt, rice, silica gel, magnesium stearate, milk powder, glycerol, propylene glycole, ethanol etc. Preferred methods for the treatment of patients is the oral, the parantheral or the rectal form. It might be useful to administer the pharmaceutical compositions several times a day or in a controlled release formulation. Veterinary compositions and use are included into the scope of the invention. Further aspects of the invention are demonstrated in the Examples without the intention of any limitation to the con¬ tents of the same. EXAMPLES I.Biological Examples Example 1.1. Female OFA-rats of 140-180 g weight were starved for 24 hours then treated orally first with different doses of the compounds to be investigated and after 60 minutes with 20 mg/kg of indomethacin. The compounds were administered in a volume of 0,5 ml/100 g in a suspension prepared in water with 2-4 % Tween-80. After 6 hours the animals were over - anesthesized and their stomachs were opened along the grea¬ ter curvature. The preparations were investigated by stereo- microscopy using an 8-fold enlargement. The number, size and incidence of erosions and ulcers was noted and compared with the control group treated with the carrier only. The size of the ulcers was determined on the basis of the following score: 1: ulcer or erosion of the size of 1-2 mm; 2: ulcer or erosion of the size of 2-3 mm; 3: ulcer or erosion of the size of 3-4 mm; 4: ulcer longer than 4 mm; 5: ulcer longer and broader than 4 mm. The ED 50 values were calculated on the basis of ulcer-indexes: /severeity of lesion x number of lesions/ ulcer index = number of animals /n/ The results are shown in Table I. Table I. Substance ED50 mg/kg (p.o.) Substance ED5omg/kg(p.o. ) N° /confidence N° /confidence limits 95 %/ limits 95 %/ 13 8 40 /7,2-15,3/ /22,8-60,2/ 53 11 14 /41,7-63,8/ /9,8-19,9/ 74 12 74 /59,6-88,4/ /54,0-86,3/ 44 47 /32,9-54,5/ /32,7-62,8/ 38 10 74 /22,4-56,8/ /58,6-89,2/ 29 cimetidin 96 /17,0-35,5/ /78-112/ 34 /21,6-48,4/ The above show that lesions caused by intomethacάn are strongly decreased by the test samples. In some cases the effect is 2-6 times stronger than the effect caused by ci¬ metidin. Example 1.2. 60 mg/kg piroxicam or 75 mg/kg naproxen were injected orally to WISTAR rats of 150-170 g weight after 24 hours of starva¬ tion. Administration of the test substances followed 1 hour after injection. After 4 hours the animals were over-anest- hesized with ether and the changes (erosions) were evaluated as in Example 1.1. The size of the lesions was characterized by way of the ulcer index. The results are shown in Table II, Table II. substance n dose ulcus index inhibition No mg/kg po. ±SEM % naproxen 7 75 25,2 + 6,1 - naproxen + 75 + 1 7 20 15,6 + 6,4 39 7 30 1,2 + 0,5** 95 piroxicam 7 60 23,3 + 6,4 piroxicam+ 60+ 1 7 20 3,8 + 0,4* 84 7 30 1,8 + 0,5** 93 ** p<0,01 p = significance * p<0,05 Table II. shows that the test samples reduce lesions caused by the NSAIDs naproxen and prixocam which are prostaglan¬ din synthesis inhibitors. Administration 1 hour after the NSAID treatment gave practically a total protection of the gastric mucous membran. Example 1.3. The pilorus of Shay rats of 150-170 g weight was tied in et¬ her narcosis /Gastroenterology 5,43,1945/. The test substan¬ ces were added on the course of operation intra-duodenally. Immediately after operation each rat obtained 0,5 ml s.c. of a physiological salt solution for hydration. After 4 hours the rats were over-anesthesized, the stomach liquid was col¬ lected, centrifugated and the volume determined. Acidity of the secretion was determined with 0,1 N aqueous sodium hy¬ droxide in the presence of a Tobfler reagent. Measurement of stimulated secretion of gastric acid was also carried out according to the above method. Immediately af¬ ter ligation of the pilorus increase of secretion was indu¬ ced by s.c. administration of 10 mg/kg of histamine,. The results are shown in Table III. Table III Substance dose volume μEqu/4 n μEqu/ml No. i.d ml control 5,26 ± 0,82 561,0 ± 0,87 107 ± 10 1 5 1,4 ± 1,24* 147,0 ± 0,19* 105 ± 5 10 0,58 ± 0,1** 42,0 ± 0,3** 61 ± 5*a * p < 0,05 ** p < 0,01 *a: it was not possible to titrate part of the secretio because of the small volume, this is why there is a differenc between the μEqu/4 n and the μEqu/ml values. Influencing histamine stimulated hydrochloric acid secretion is shown in Table IV: Table IV. substance dose volume/4 h μEqu/4 h μEqu/ml N°. mg/kg ml basal secretion 4,5 ± 0,6 575 ± 60 128 + 11 histamine 10(s.c. ) 6,3 ± 0,7 1477 ± 80 237 ± 18 histamine+1 10(s.c. ) 5(i.d. ) 1,7 ± 0,2* 180 ± 12*" ' 105 + 10* 10(i.d. ) 0,9 ± 15** 111 ± 9** 123 + 8* * p < 0,05 ** p < 0,01 Table III. and IV. demonstrate that both the basic gastric acid secretion and the acid secretion stimulated with hista¬ mine were inhibited by the test samples. Example 1.4. Female rats of 120-130 g weight, subjected to starvation for 24 hours were treated perorally with different doses of the test substances and after 30 minutes with hydrochloric acid in ethanol (1 ml of concentrated hydrochloric acid in 50 ml of absolute ethanol). The volume of treatment was 0,5 ml/100 g. After 1 hour the animals were over-anesthesized, the average length of haemorrhages of the gastric glandular parts were measured with mm accuracy. The average degree of haemorrhages of the treated groups was compared to the con¬ trol groups treated with the vehicle only. Number of animals was 6-18 in each group. The results are shown in Table V. Table V. Substance dose number of animals average length of haemmorrhages mg/kg control treated control treated in? 2,3 12 12 95,7±9,4 91,0±9,4 -4 5,0 18 18 92,9±6,3 39,7±8,1 -57 10,0 18 18 61,3±9,8 14,2±7,4 -77 6 20,0 6 6 61,3±9,8 48,0±10,3 -22 11 20,0 12 12 80,4±8,2 51,8±10,0 -36 cimetidin 100 cimetidin 300 16 16 74,8±6,4 64,2±12,3 -24 ± SE change It is shown above that the test samples protected the gast¬ ric mucous membran in a dose-dependent manner against lesi¬ ons induced with hydrochloric acid and ethanol. Cimetidin was practically inactive at 100 mg/kg doses. Example 1.5. The method of Szabo & et. al (Gastroenterology, 88, 228, 1985) was used for evaluation of alcohol induced increase of gastric glandular capillary permeability on rats. 15 minutes after administration of the test samples a 0,5 % solution of methylene blue in water was injected i.v. After 13 minutes 1 ml of 100 % ethanol was added perorally and after further 2 minutes the stomachs were removed and their weights measu¬ red. As a consequence of capillary lesions the methylene blue leaved the vascular bed, resulting in an increased blue coloration of the stomach. In order to extract the co¬ lour the glandular part was extracted for 24 hours in a so¬ lution of 1 % sumarin in raethanol and intensity of the co¬ lour was determined by way of photometry at 615 nm wave length after centrifugating the solution obtained. The re¬ sults are shown in Table VI. Table VI. substance dose mg/kg stomach (g) Evans-blue μg/g 100% ethanol 1,1 ± 0,15 9,45 ± 0,94 100% ethanol + 1 20 0,93 ± 0,1 4,4 ± 0,23' 10 0,91 ± 0,1 4,55 ± 0,3' * = p < 0,05 The results show that alcohol-induced lesions are reduced by administration of substance 1. Example 1.6. To investigate inhibition of stress ulcer caused by imme¬ rsion Wistar rats of both sexes of 180-200 g weight were placed into a water bath of 20±1°C 30 minutes after peroral treatment with the test substance, vertically to the level of the xiphoid process. After seven hours the glandular le¬ sions appearing in the stomach were evaluated according to the score described in Example 1.1. The results are shown in Table VII. It is evident that 50mg/kg doses of substance 1. significally inhibit hyperemia and erosion. Cimetidin caused no significant inhibition. Table VII Substance dose n hyperemiia erosion N° mg/kg ulcer- inhibi- ulcus- inhibi¬ p.o. index mm tion % index mm tion % control 10 80.1 + 7.3 42,4 + 8.3 1 10 7 64.3 ± 8,6 29 33.6 + 10.2 21 25 10 35.8 ± 9,4 55** 12.1 + 3.6 71** 50 7 11.4 + 2.8 85** 5.7 + 1.5 87** control 73.4 ± 6,9 36.9 + 7.2 cimetidin 100 7 58.1 + 10.4 21 24,4 ± 10.0 34 200 7 48.2 + 14.6 39 18.2 + 11.2 50 ** = p < 0,01 Example 1.7. To investigate influence of gastric blood-supply the tests were carried out according to the method of Sapirstain using Rb86 isotopes (Circ.Res.4, 689, 1956; Am. J. Physiol. 193. 161,1958). The test substances were administered pero¬ rally 2 hours before the experiment started and the degree of blood flow was determined in ml/min/g values. In the ex¬ periments the stomachs of Wistar female rats were divided into three segments i.e. pre-stomach, corpus and anthrum. The results are shown in Table VIII. Table VIII illustrates that the test samples increase bloo flow in the gastric body and anthrum while there was no change in the pregastric region. Table VIII, substance dose n blood flow ml/min/σ ± SE No. mg/kg pre-stomach corpus anthrum control 11 0.23 ± 0.03 0.51 ± 0.03 0,71 ± 0,0 1 100 11 0.19 ± 0,01 0.70 ± 0.09* 1.01 ± 0.0 * = p < 0,02 Example 1.8. Female OFA rats of 130-160 g weight, starved for 24 hours, were treated at the same time perorally with 40 mg/kg doses of the substances to be tested and with 5 mg/kg s.c. doses of reserpine. After 18 hours the animals were over-anesthe- sized and the removed stomachs were investigated under ste- reomicroscope using a 8-fold enlargement. The number of ul¬ cers was counted and their size was evaluated using 0 - 0,5 - 1 - 2 - 4 - 8 - 16 -32 scores. The number of animals was 5 for each dose. Results (%change compared with control) are shown in Table IX. Table IX. substance N° mg/kg number of severity of ulcers per ulcers ulcers treated 1 40 + 4 + 9 5/5 6 40 +17 - 5 5/5 11 40 +67 +37 5/5 Table IX. demonstrates that the number and severeity of ul¬ cers is not decreased by the test samples, as compared to the control, thus they are ineffective against ulcers indu¬ ced by reserpine. This indicates that their ulcer inhibiti¬ ng activity is not a result of an influence on the cholinerg system. Example I . 9 To determine acute toxicity the test substances were admi¬ nistered in increasing doses to CFLP male mice (18 -20 g) and to male Wistar rats (150 - 160 g) . The LD50 values were calculated after 14 days of observation according to Litch- field and Wilcoxon. The results are chown in Table X: Table X substance species LD5 0 mg/kg per os 1 mice 840 (720 - 890) rats 560 (480 - 610) II. Examples for compositions Example II.1. Composition for intravenous injection Components: Active ingredient of general formula (I) 0,03 g (e.g. Substance N°l to 10) Propylene glycole 20,0 g Polyethylene glycole 400 20,2 g Tween 80 1,2 g 0,9 % Aqueous solution of sodium chloride ad 1000,0 ml. Method: The active ingredient is dissolved in the mixture of propylene glycole, polyethylene glycole and Tween 80 whereu¬ pon the amount of an aqueous solution containing 0,9 % of sodium chloride needed to complete the volume to 1000 ml is added. The solution is filtered on a membran filter of 0,2 μ pore size and filled into ampoules under sterile conditions. Example II.2. Capsules Components: Active ingredient 250 mg Magnesium stearate 20 mg The above components are admixed dry and filled into cap sules of 500 μl volume. Example II.3. Tablets Components: Active ingredient 100 mg Cellulose 10 mg Lactose 20 mg Magnesium stearate 2 mg Polyvinyl-pyrrolidone /PVP/ 3 mg Granules containing the active ingredient are prepared by kneading the active ingredient with cellulose, lactose and a solution of PVP in ethanol. The granules obtained are dried, mixed with magnesium stearate and the tablet-material is pressed to form tablets in the usual manner. III. Chemical Examples Example III.l. 3,27 g of 4-chloro-quinoline, 1,38 g of lH-l,2,4-triazole and 0,21 g of lH-l,2,4-triazole hydrochloride are mixed in 10 ml of dimethyl-formamide for 1 hour at 80 °C. The reacti¬ on mixture is added to 50 ml of water, neutralized with cc. aqueous ammonia, the precipitate is filtered, washed with water and recrystallized from 15 ml of ethanol. 2,47 g /63%/ of 4-(1H-1,2,4-triazole-l-yl)-quinoline (Substance 1) are obtained. M.p.: 147 - 149°C. Example III.2. 1,98 g of 4,7-dichloro-quinoline and 1,38 g of 1H-1,2,4- triazole are reacted in 10 ml of dimethyl formamide and wor¬ ked up as described in Example 1. 2,6 g of 4-(lH-l,2,4-tria- zole-l-yl)-7-chloro-quinoline (Substance 2) are obtained. M.p. : 169 - 170°C. Example III.3. 1,64 g of 2-chloro-quinoline and 1,1 g of the sodium salt of lH-l,2,4-triazole are reacted in 10 ml of dimethyl formamide for 20 hours at 100 °C and worked up as in Example 1 to give 1,43 g of 2-(1H-1,2,4-triazole-l-yl)-quinoline /yield 53 %/ M.p.: 107 - 109 β C. (Substance 5). Using similar methods along with the suitable starting mate¬ rials the following products are obtained: Ex. N° Product Yield% M.p. °C 111.4. 3. 4-(lH-l,2,4-triazole-l-yl)- -7-methyl-quinoline 69 179 - 180 111.5. 4. 2-methyl-4-(lH-l,2,4-triazole- -1-yl)-quinoline 62 95 - 96 111.6. 6. 2-(lH-l,2,4-triazole-l-yl)- -3-methyl-quinoline 69 87 - 89 111.7. 7. 2-(lH-l,2,4-triazole-l-yl)- -3-methyl-7-bromo-quinoline 92 122 - 123 111.8. 8. 2-(lH-l,2,4-triazole-l-yl)- -3-methyl-7-ethyl-quinoline 64 72 - 73 111.9. 9. 2-methyl-4-(lH-l,2,4-triazole- -3-yl-thio)-quinoline 89 180 - 182 111.10 10. 2,5,7-trimethyl-4-(5-ethyl-lH- -1,2,4-triazole-3-yl-thio)- -quinoline 69 198 - 201 111.11 11. 2-(lH-l,2,4-triazole-3-yl- -thio)-3-methyl-quinoline 83 150 - 151 111.12 12. 2-(5-ethyl-lH-l,2,4-triazole- 3-yl-thio)-3-methyl-quinoline 85 187 - 189 Example III.13. 3,21 g of 4-(lH-2,3,4-triazole-l-yl)-quinoline-hydrochlo- ride are obtained (Substance N°l.HCl) from the crude product of Example 1. with HCl in ethanol. Yield: 69%. M.p.: 238- 240°C.

Claims: Claims ^ 1. Pharmaceutical composition for the treatment or prevention of lesions of gastrointestinal mucous membrans and having secretion inhibiting, cytoprotective activities c h a r a c t e r i z e d b y its containing in a biolo¬ gically effective quantity a triazole-group-substituted quinoline derivative of general formula (I) -R 1 stands for a 1-triazolyl-group in position 2 or 4 or a 3-triazolyl-thio or a 5-/Cι-4-alkyl/-3-triazolyl-thio-group, -R 2 stands for a hydrogen atom in position 3 or op¬ tionally in position 2, or for a Cι- 4 -alkyl-group, -R3 stands for a hydrogen atom or for a Cι- 4 -alkyl- group, -X stands for a hydrogen or halogen-atom or for a C 1 - 4 - alkyl-group - or its salts. 2. Pharmaceutical composition for the treatment or prevention of lesions of gastrointestinal mucous membrans and having secretion inhibiting, cytoprotective activities c h a r a c¬ t e r i z e d b y its containing a quinoline derivative of general formula (II) - R 1 , R 2 , R3 and X stand for the same as above - or its salts in a biologically effective quantity. 3. Pharmaceutical composition for the treatment or prevention of lesions of gastrointestinal mucous membrans and having secretion inhibiting, cytoprotective activities c h a r a c¬ t e r i z e d b y its containing a quinoline derivative of general formula (III) - R 1 , R 2 , R 3 and X stand for the same as above - or its salts in a biologically effective quantity. 4. Pharmaceutical composition sccording to claims 1 to 3 c h a r a c t e r i z e d b y its containing at least one of the following quinoline derivatives or its salt in a bio¬ logically effective quantity: 4- 1H-1,2,4-triazole-l-yl)-quinoline, 4- 1H-1,2,4-triazole-l-yl)-7-halogen-quinolines, 4- 1H-1,2,4-triazole-l-yl)-7-chloro-quinoline, 4- 1H-1,2,4-triazole-l-yl)-7-(Cι-4alkyl)-quinolines, 2-methyl-4-(1H-1,2,4-triazole-l-yl)-quinoline, 2-(1H-1,2,4-triazole-l-yl)-quinoline, 2-(1H-1,2,4-triazole-l-yl)-3-(Cι_4alkyl)-quinolines, 2-(1H-1,2,4-triazole-l-yl)-3-methyl-quinoline, 2-(1H-1,2,4-triazole-l-yl)-3-(Cι-4alkyl)-7-halogen- quinolines, 2-(1H-1,2,4-triazole-l-yl)-3-methyl-7-bromo-quinoline, 2-(1H-1,2,4-triazole-l-yl)-3-methyl-7-chloro-quinoline, 2-(lH-l,2,4-triazole-l-yl)-3-(Cι_ 4 alkyl)-7-(Cι- 4 alkyl)- quinolines, 2-(1H-1,2,4-triazole-l-yl)-3-methyl-7-ethyl-quinoline, 2-(Cι-4alkyl)-4-(lH-l,2,4-triazole-l-yl-thio)- quinolines, 2,5,7-trimethyl-4-(5-ethyl-lH-l,2,4-triazole-3-yl-thio)-quinoli 2- 1H-1,2,4-triazole-3-yl-thio)-3-(Cι-4alkyl)-quinolines, 2- 5-ethyl-lH-l,2,4-triazole-3-yl-thio)-3-methyl-quinoline, 2- 1H-1,2,4-triazole-3-yl-thio)-3-methyl-quinoline. 5. Pharmaceutical composition according to claims 1 to 4 c h a r a c t e r i z e d b y its containing a quinoline derivative of general formula (II) - Rl, R2. R3 and X stand for the same as above - or its salts in a biologically effective quantity, together with inert, pharmaceutically acceptable accompanying pro- ducts or in admixture with the same. 6. Process for the preparation of pharmaceutical compositions according to claims l to δ c h a r a c t e r i z e d b y formulating the quinoline derivative of general formula (II) - R 1 , R 2 , R3 and X stand for the same as above - or its salts by admixture with accompanying and/or additive products usually used in pharmaceutical production. 7. Method for the treatment or prevention of lesions of gast¬ rointestinal mucous membrans, for inhibiting secretion or for cytoprotection especially for the treatment or preventi¬ on of ulcer, c h a r a c t e r i z e d b y administering to the patient in need of such treatment a quinoline deri¬ vative of general formula (I) - R l , 2, R 3 and X stand for the same as above - or its salts or a composition containing the same prefe rably orally, parentherally or rectally, in a daily dose of 5 to 30 mg active ingredient per kg body weight. 8. A composition or a method of treatment according to any of claims 1 to 7 c h a r a c t e r i z e d b y its contai¬ ning also an active ingredient having antiinflammatory ac¬ tivity or its use together with the same whereby the quino¬ line derivatives of general formula (I) ~ Rl, 2, R3 and X stand for the same as above - are administered before, together or after treatment with the antiinflammatory agents. 9. A composition or a method of treatment according to claim 8 c h a r a c t e r i z e d b y using as an antiinflammatory agent NSAIDs such as indomethacin, piroxicam, naproxen, sa- licilates, ibuprofen, diclofenac and the like. 10. 4-(lH-l,2,4-triazole-l-yl)-quinoline and its salts.

Inventors: BILKEI-GORZO ANDRAS, FRANK LASZLO, GALAMB VILMOS, GYIRES KLARA, KORODI FERENC, BILKEI-GORZO, ANDRAS, FRANK, LASZLO, GALAMB, VILMOS, GYIRES, KLARA, KORODI, FERENC
Applicants: ALKALOIDA VEGYESZETI GYAR, BILKEI GORZO ANDRAS, FRANK LASZLO, GALAMB VILMOS, GYIRES KLARA, KORODI FERENC, ALKALOIDA VEGYESZETI GYAR RT., BILKEI-GORZO, ANDRAS, FRANK, LASZLO, GALAMB, VILMOS, GYIRES, KLARA, KORODI, FERENC
Application year: 1994
Main classification: A61K31
IPC codes: A61K31, A61P1, C07D401, C07D521